OBJECTIVE: To explore associations between temperature, humidity and hand, foot and mouth disease (HFMD) incidence in Guangzhou, China from 2013 to 2017. METHODS: A distributed lag non-linear model was applied to estimate the effects of daily temperature and humidity on HFMD incidence after adjusting for long-term trends, seasonal trends, and day of the week. RESULTS: In total, 353,431 confirmed HFMD cases were reported in Guangzhou over the study period. A bimodal seasonal pattern was observed. High temperatures had acute short-term effects on HFMD incidence that declined quickly over time. The effects of low humidity declined over lag periods, but increased when the humidity surpassed 60.5%. Temperature and humidity were both inversely associated with HFMD incidence during lag days 0 to 3 and with lag periods. CONCLUSIONS: Temperature and humidity play important roles in HFMD incidence. These data are important for developing public health strategies.